Estudio observacional con certolizumab pegol de 12 semanas de duración en pacientes con artritis reumatoide con y sin exposición previa a anti-TNF: resultados ecográficos, clínicos y reportados por los pacientes

[Abstract] Objectives: To assess the effectiveness and safety of certolizumab pegol (CZP) in Spanish patients with RA. Materials and methods: SONAR (NCT01526434), a 12-week, open-label, prospective, observational, multicenter study. Patients with active RA for ≥3 months, according to ACR criteria, were treated with CZP (400mg at Weeks 0, 2 and 4, then 200mg every 2 weeks). The primary effectiveness endpoint was change from baseline (CFB) in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12. Other assessments included DAS28(ESR), patient's assessment of arthritis pain (PtAAP-VAS) and Short Form 36-item Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS). Joint inflammation was investigated using Power Doppler (PD) ultrasound (US), to detect effusion, synovial hypertrophy and synovial PD signal. PDUS outcomes assessed CFB to Week 12 in synovial hypertrophy, effusion and PD signal indices. Results: A total of 77/80 enrolled patients received ≥1 dose of CZP. The 12-week mean reduction from baseline (SD) was -0.6 (0.6) for HAQ-DI and -2.2 (1.5) for DAS28(ESR). PtAAP-VAS was reduced from baseline (mean [SD]: -36.8 [26.8]) and improvements in SF-36 PCS and SF-36 MCS were reported. Synovial hypertrophy, effusion and PD signal indices were reduced from baseline to Week 12. One death was reported during the study. Conclusions: Spanish patients with RA demonstrated improvements in clinical, PDUS and patient-reported outcomes over 12 weeks of CZP treatment. No new safety signals were identified, and the safety profile was in line with previous CZP studies. These results support previous clinical trial findings investigating CZP treatment for active RA.[Resumen] Objetivos: Evaluar la eficacia y la seguridad de certolizumab pegol (CZP) en pacientes españoles con artritis reumatoide (AR). Materiales y métodos: SONAR (NCT01526434), un estudio multicéntrico, observacional, prospectivo, abierto de 12 semanas. Pacientes con AR activa ≥3 meses, según criterios ACR, recibieron CZP (400 mg en las semanas 0, 2 y 4, seguido de 200 mg cada 2 semanas). La variable principal de eficacia fue el cambio desde el inicio (CDI) en el HAQ en la semana 12. Otras evaluaciones incluían el DAS28-VSG, la valoración del dolor (PtAAP-VAS) y el componente físico (PCS) y mental (MCS) del SF-36. La inflamación articular se estudió utilizando ecografía con Power Doppler (PDUS) midiendo derrame, hipertrofia sinovial y señal PD sinovial. Los resultados de PDUS evaluaron el CDI hasta la semana 12 en índices de hipertrofia sinovial, derrame y PD. Resultados: Un total de 77/80 pacientes recibieron ≥una dosis de CZP. La reducción media en 12 semanas desde el inicio (DE) fue de −0,6 (0,6) para HAQ y de −2,2 (1,5) para DAS28-VSG. La PtAAP-VAS disminuyó desde el inicio (media [DE]: −36,8 [26,8]) y hubo mejorías en los componentes PCS y MCS del SF-36. Los índices de señales de hipertrofia sinovial, derrame y PD disminuyeron desde el inicio hasta la semana 12. Se notificó una muerte durante el estudio. Conclusiones: Los pacientes españoles con AR mostraron mejoras en resultados clínicos, PDUS y notificados por el paciente durante 12 semanas de tratamiento con CZP. No hubo nuevas señales de seguridad, y el perfil de seguridad estaba en línea con estudios previos. Estos resultados respaldan los hallazgos de ensayos clínicos previos de CZP en AR

Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas

Obtained from Haematologica/the Hematology Journal website http://www.haematologica.orgPeripheral T-cell lymphomas are very aggressive hematologic malignancies for which there is no targeted therapy. New, rational approaches are necessary to improve the very poor outcome in these patients. Phosphatidylinositol- 3-kinase is one of the most important pathways in cell survival and proliferation. We hypothesized that phosphatidylinositol- 3-kinase inhibitors could be rationally selected drugs for treating peripheral T-cell lymphomas. Several phosphatidylinositol-3-kinase isoforms were inhibited genetically (using small interfering RNA) and pharmacologically (with CAL-101 and GDC-0941 compounds) in a panel of six peripheral and cutaneous T-cell lymphoma cell lines. Cell viability was measured by intracellular ATP content; apoptosis and cell cycle changes were checked by flow cytometry. Pharmacodynamic biomarkers were assessed by western blot. The PIK3CD gene, which encodes the δ isoform of phosphatidylinositol-3-kinase, was overexpressed in cell lines and primary samples, and correlated with survival pathways. However, neither genetic nor specific pharmacological inhibition of phosphatidylinositol-3-kinase δ affected cell survival. In contrast, the pan-phosphatidylinositol-3-kinase inhibitor GDC-0941 arrested all T-cell lymphoma cell lines in the G1 phase and induced apoptosis in a subset of them. We identified phospho-GSK3b and phospho-p70S6K as potential biomarkers of phosphatidylinositol-3-kinase inhibitors. Interestingly, an increase in ERK phosphorylation was observed in some GDC-0941-treated T-cell lymphoma cell lines, suggesting the presence of a combination of phosphatidylinositol-3-kinase and MEK inhibitors. A highly synergistic effect was found between the two inhibitors, with the combination enhancing cell cycle arrest at G0/G1 in all T-cell lymphoma cell lines, and reducing cell viability in primary tumor T cells ex vivo. These results suggest that the combined treatment of pan-phosphatidylinositol-3-kinase + MEK inhibitors could be more effective than single phosphatidylinositol-3-kinase inhibitor treatment, and therefore, that this combination could be of therapeutic value for treating peripheral and cutaneous T-cell lymphomas.This work was supported by grants from the Asociación Española Contra el Cáncer, Fondo de Investigaciones Sanitarias (PI051623, PI052800 and PI080856), RTICC (RD06/0020/0107) and Ministerio de Ciencia e Innovación (SAF2008-0387-1). EMS is supported by a grant from the Department of Education, Universities and Research of the Basque Government (BFI08.207). MSB is supported by a Contract Miguel Servet from Fondo de Investigaciones Sanitarias (CP11/00018

PREVALENCIA DE Cryptosporidium parvum EN ESCOLARES DE SONORA, MEXICO

La criptosporidiosis es un problema de salud pública, afectando principalmente a personas inmunocomprometidas, niños y ancianos. Esta infección tiene diferentes factores causales y se le ha asociado con altas tasas de morbilidad en la población afectada. Criptosporidiosis es cosmopolita, pero su prevalencia es más alta en sociedades subdesarrollada aunque actualmente la misma se desconoce en México. El objetivo de este estudio fue determinar la prevalencia actual de Cryptosporidium parvum (C. parvum) en una subpoblación de escolares del municipio de Hermosillo, Sonora, México. Se usó ELISA para detectar antígenos fecales de C. parvum. Se invitó a participar a 720 escolares registrados oficialmente en tres primarias públicas. 175 niñas y 145 niños, de edades entre 6 a 13 años participaron voluntariamente durante septiembre a diciembre 2008. De los 320 escolares estudiados, 121 (37,8 %) mostraron infección por C. parvum. No se encontró diferencia en la prevalencia de criptosporidiosis entre sexos (p = 0,15), ni entre áreas suburbana y rural (p = 0,18). Se observó un aumento de la infección con la edad en este estudio. Criptosporidiosis quizá es un serio problema de salud pública en el estado de Sonora y se requieren estudios adicionales que lo confirmen para que las autoridades responsables puedan prevenir y controlar la infección

Activating Transcription Factor 4 Modulates TGFβ-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 Signaling

Purpose: On the basis of the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFβ1. ATF4 is overexpressed in patients with triple-negative breast cancer (TNBC), but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine ATF4 effects on patients with breast cancer survival and TNBC aggressiveness, and the relationships between TGFβ and ATF4. Defining the signaling pathways may help us identify a cell signaling-tailored gene signature.Experimental Design: Patient survival data were determined by Kaplan-Meier analysis. Relationship between TGFβ and ATF4, their effects on aggressiveness (tumor proliferation, metastasis, and stemness), and the underlying pathways were analyzed in three TNBC cell lines and in vivo using patient-derived xenografts (PDX).Results: ATF4 overexpression correlated with TNBC patient survival decrease and a SMAD-dependent crosstalk between ATF4 and TGFβ was identified. ATF4 expression inhibition reduced migration, invasiveness, mammosphere-forming efficiency, proliferation, epithelial-mesenchymal transition, and antiapoptotic and stemness marker levels. In PDX models, ATF4 silencing decreased metastases, tumor growth, and relapse after chemotherapy. ATF4 was shown to be active downstream of SMAD2/3/4 and mTORC2, regulating TGFβ/SMAD and mTOR/RAC1-RHOA pathways independently of stress. We defined an eight-gene signature with prognostic potential, altered in 45% of 2,509 patients with breast cancer.Conclusions: ATF4 may represent a valuable prognostic biomarker and therapeutic target in patients with TNBC, and we identified a cell signaling pathway-based gene signature that may contribute to the development of combinatorial targeted therapies for breast cancer

An Energy-Reduced Mediterranean Diet, Physical Activity, and Body Composition

[ENG]Importance Strategies targeting body composition may help prevent chronic diseases in persons with excess weight, but randomized clinical trials evaluating lifestyle interventions have rarely reported effects on directly quantified body composition. OBJECTIVE To evaluate the effects of a lifestyle weight-loss intervention on changes in overall and regional body composition. DESIGN, SETTING, AND PARTICIPANTS The ongoing Prevención con Dieta Mediterránea-Plus (PREDIMED-Plus) randomized clinical trial is designed to test the effect of the intervention on cardiovascular disease prevention after 8 years of follow-up. The trial is being conducted in 23 Spanish research centers and includes men and women (age 55-75 years) with body mass index between 27 and 40 and metabolic syndrome. The trial reported herein is an interim subgroup analysis of the intermediate outcome body composition after 3-year follow-up, and data analysis was conducted from February 1 to November 30, 2022. Of 6874 total PREDIMED-Plus participants, a subsample of 1521 individuals, coming from centers with access to a dual energy x-ray absorptiometry device, underwent body composition measurements at 3 time points. INTERVENTION Participants were randomly allocated to a multifactorial intervention based on an energy-reduced Mediterranean diet (MedDiet) and increased physical activity (PA) or to a control group based on usual care, with advice to follow an ad libitum MedDiet, but no physical activity promotion. MAIN OUTCOMES AND MEASURES The outcomes (continuous) were 3-year changes in total fat and lean mass (expressed as percentages of body mass) and visceral fat (in grams), tested using multivariable linear mixed-effects models. Clinical relevance of changes in body components (dichotomous) was assessed based on 5% or more improvements in baseline values, using logistic regression. Main analyses were performed in the evaluable population (completers only) and in sensitivity analyses, multiple imputation was performed to include data of participants lost to follow-up (intention-to-treat analyses). RESULTS A total of 1521 individuals were included (mean [SD] age, 65.3 [5.0] years; 52.1% men). In comparison with the control group (n=761), participants in the intervention arm (n=760) showed greater reductions in the percentage of total fat (between group differences after 1-year, −0.94% [95% CI, −1.19 to −0.69]; 3 years, −0.38% [95% CI, −0.64 to −0.12] and visceral fat storage after 1 year, -126 g [95% CI, −179 to −73.3 g]; 3 years, −70.4 g [95% CI, −126 to −15.2 g] and greater increases in the percentage of total lean mass at 1 year, 0.88% [95% CI, 0.63%-1.12%]; 3-years 0.34% [95%CI, 0.09%-0.60%]). The intervention group was more likely to show improvements of 5% or more in baseline body components (absolute risk reduction after 1 year, 13% for total fat mass, 11% for total lean mass, and 14% for visceral fat mass; after 3-years: 6% for total fat mass, 6% for total lean mass, and 8% for visceral fat mass). The number of participants needed to treat was between 12 and 17 to attain at least 1 individual with possibly clinically meaningful improvements in body composition. CONCLUSIONS AND RELEVANCE The findings of this trial suggest a weight-loss lifestyle intervention based on an energy-reduced MedDiet and physical activity significantly reduced total and visceral fat and attenuated age-related losses of lean mass in older adults with overweight or obesity and metabolic syndrome. Continued follow-up is warranted to confirm the long-term consequences of these changes on cardiovascular clinical end points.S

Dendritic cell deficiencies persist seven months after SARS-CoV-2 infection

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFN-α production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin β7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19

Establecimiento del tamaño de raciones de consumo de frutas y hortalizas para su uso en guías alimentarias en el entorno español: propuesta del Comité Científico de la Asociación 5 al día

Introduction: Food servings are standard amounts of food stuffs or drinks to help dietetic advice to promote and preserve health. The aim is to establish the serving size of fruits and vegetables (FH) to be used in food based dietary guidelines (FBDG). Material and Methods: Methodology of the United States Department of Agriculture (USDA) was adapted to establish serving sizes for FBDG, along of the followed by the food exchange system. Data was collected from the FH portion sizes reported in nutritional surveys and common sizes available in the Spanish market, and they were adjusted to an easily recognisable quantities of food with equivalence on key nutrients: the compliance with public health goals for FH consumption was evaluated. Results: Portion sizes typically reported in Spanish nutrition surveys are scarce and not homogeneous, and no data published in scientific journals on portion sizes were available. The Spanish FBDG, in spite of showing a range of serving size for FH, do not assure that they are interchangeable nor specify the method to obtein them.The serving of vegetables was 139,44g (DS:+/- 21.98, CV:0.16), 137,68g (DS:+/- 49,61, CV:0,36) for fruits and 28.00g (DS:+/- 7,53, CV:0.27) for dried fruits. Conclusions: With the established servings, the recommendation of consuming "at least 5 servings of FH a day" would allow reaching the Public Health goals for FH established in 600g (net weight)/person/day. It is recommended that the Spanish Agency for Consumers, Food Safety and Nutrition (AECOSAN) uses this methodology to establish serving sizes for the rest of food groups that make up the FBDG for the Spanish population.Introducción: Las raciones de consumo son cantidades estándar de alimentos o bebidas sugeri-das para asesorar sobre la cantidad de alimento a consumir para preservar un estado de salud adecuado. El objetivo principal de este trabajo es establecer los tamaños de ración de consumo de frutas y hortalizas (FH) para uso en guías alimentarias.Material y Métodos: Se adaptó la metodología de la United States Department of Agriculture (USDA) para el establecimiento de los tamaños de ración de consumo para guías, y la del Sistema de Intercambios. Se recopilaron datos de porción reportados en encuestas y calibres comunes en el mercado, se ajustó a cantidades de alimento fácilmente reconocibles y con equivalencia de nutrientes clave y se evaluó el grado de cumplimiento de los objetivos de salud pública para el consumo de FH. Resultados: Los tamaños de porción típicamente reportados en encuestas españolas son escasos y poco homogéneos, y no se encontraron datos publicados en revistas científicas sobre los cali-bres. Las guías alimentarias españolas, a pesar de mostrar un rango de tamaño de ración para FH no aseguran que sean intercambiables ni especifican el método para llegar a las mismas. La ración de hortalizas obtenida ha sido de 139,44g (DS:±21,98; CV:0,16), de 137,68g (DS:±49,61; CV:0,36) para frutas y 28,00g (DS:±7,53; CV:0,27) para frutas desecadas. . Conclusiones: Con las raciones establecidas, el mensaje “consume al menos 5 raciones entre FH al día” permitiría alcanzar los objetivo de Salud Pública para FH establecidos en 600g (peso neto)/persona/día. Se recomienda a la Agencia Española de Consumo, Seguridad Alimentaria y Nutrición (AECOSAN) que use esta misma metodología para el establecimiento de raciones en el resto de grupos de alimentos que configuran la Guía Dietética Basada en Alimentos para la población española

The wide-field, multiplexed, spectroscopic facility WEAVE: Survey design, overview, and simulated implementation

WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366$-$959\,nm at $R\sim5000$, or two shorter ranges at $R\sim20\,000$. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for $\sim$3 million stars and detailed abundances for $\sim1.5$ million brighter field and open-cluster stars; (ii) survey $\sim0.4$ million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey $\sim400$ neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in $z<0.5$ cluster galaxies; (vi) survey stellar populations and kinematics in $\sim25\,000$ field galaxies at $0.3\lesssim z \lesssim 0.7$; (vii) study the cosmic evolution of accretion and star formation using $>1$ million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at $z>2$. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator.Comment: 41 pages, 27 figures, accepted for publication by MNRA